Mitochondrial fission is an acute and adaptive response in injured motor neurons.

Sumiko Kiryu-Seo,Katsuyoshi Mihara,Masatoshi Nomura,Yukina Kato,Hiromi Tamada,Katsura Yasuda,Naotada Ishihara,Hiroshi Kiyama

doi:10.1038/srep28331

Sumiko Kiryu-Seo, Katsuyoshi Mihara + Show 6 more

Open Access

https://doi.org/10.1038/srep28331

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Abstract

Successful recovery from neuronal damage requires a huge energy supply, which is provided by mitochondria. However, the physiological relevance of mitochondrial dynamics in damaged neurons in vivo is poorly understood. To address this issue, we established unique bacterial artificial chromosome transgenic (BAC Tg) mice, which develop and function normally, but in which neuronal injury induces labelling of mitochondria with green fluorescent protein (GFP) and expression of cre recombinase. GFP-labelled mitochondria in BAC Tg mice appear shorter in regenerating motor axons soon after nerve injury compared with mitochondria in non-injured axons, suggesting the importance of increased mitochondrial fission during the early phase of nerve regeneration. Crossing the BAC Tg mice with mice carrying a floxed dynamin-related protein 1 gene (Drp1), which is necessary for mitochondrial fission, ablates mitochondrial fission specifically in injured neurons. Injury-induced Drp1-deficient motor neurons show elongated or abnormally gigantic mitochondria, which have impaired membrane potential and axonal transport velocity during the early phase after injury, and eventually promote neuronal death. Our in vivo data suggest that acute and prominent mitochondrial fission during the early stage after nerve injury is an adaptive response and is involved in the maintenance of mitochondrial and neuronal integrity to prevent neurodegeneration.

Highlights

IntroductionThe difference between in vivo and in vitro environments, confounds understanding of the functional significance of mitochondrial dynamics under neuronal stress
These findings demonstrate that even Drp1-deficient longer mitochondria can be motile and transported in a similar way to shorter mitochondria in activating transcription factor 3 (Atf3):bacterial artificial chromosome (BAC) Tg mice during at least the first 3 days after injury; longer mitochondria gradually lose this ability and it is lost by 7 days after injury
Using this unique BAC Tg mouse, we found that mitochondrial dynamics was spatially and temporally regulated following nerve injury and that mitochondrial fission was necessary for this response, at the initial stage after nerve injury

Summary

Introduction

The difference between in vivo and in vitro environments, confounds understanding of the functional significance of mitochondrial dynamics under neuronal stress. To ensure responsiveness to nerve injury, we employed a regulatory element of the activating transcription factor 3 (Atf3) gene, which we have characterised as a unique nerve injury-responsive transcription factor[3,31,32,33]. Using this BAC Tg mouse, we can investigate how mitochondria behave in response to nerve injury and how this behaviour influences neuronal status. Drp[1] ablation in injured neurons demonstrates that mitochondrial fission at the early stage after injury is an important event for maintaining neuronal and mitochondrial integrity

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Conclusion